Increased All-Cause Mortality in Patients With Type 1 Diabetes and High-Expression Mannan-Binding Lectin Genotypes: A 12-Year Follow-up Study

Østergaard, Jakob Appel; Thiel, Steffen; Lajer, Maria; Steffensen, Rudi; Parving, Hans-Henrik; Flyvbjerg, Allan; Rossing, Peter; Tarnow, Lise; Hansen, Troels Krarup

doi:10.2337/dc15-0851

Cited by 27 publications

(18 citation statements)

References 35 publications

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“…Furthermore, serum levels of MBL are significantly elevated in patients with type 1 diabetes when comparing to healthy individuals [5, 28]. Furthermore, our group have recently described that all-cause mortality is strongly associated with MBL genotype and MBL concentration in type 1 diabetes [29]. …”

Section: Discussionmentioning

confidence: 99%

Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin

Axelgaard

Østergaard

Thiel

et al. 2017

Journal of Diabetes Research

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Mannan-binding lectin (MBL) has been reported to be involved in the pathophysiology of diabetic nephropathy. MBL is a pattern-recognition molecule of the innate immune system that initiates the lectin pathway of the complement system upon recognition of evolutionary conserved pathogen-associated molecular patterns or to altered self-tissue. Our group have previously shown direct effects of MBL on diabetes-induced kidney damage, and we hypothesized that MBL may cause autoactivation of the complement system via binding to neoepitopes induced by hyperglycemia. In the present study, we induced diabetes in MBL knockout mice and in wild type C57BL/6J mice by low-dose streptozotocin injection and measured blood glucose and urine albumin-to-creatinine ratio to monitor development of diabetes. After 24 weeks, fluorescently labelled recombinant MBL was injected intravenously in diabetic MBL knockout mice after which the distribution was investigated using in vivo fluorescence imaging. Mice were subjected to in vivo and ex vivo imaging 24 hours after injection. MBL was found to accumulate in the kidneys of diabetic mice as compared to healthy control mice (p < 0.0001). These findings support the hypothesis of a significant role of MBL and the complement system in the pathophysiology of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin

Axelgaard

Østergaard

Thiel

et al. 2017

Journal of Diabetes Research

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“…MBL levels are elevated in both patients with type 1 diabetes and type 2 diabetes , and in the last decade increased MBL and ficolin levels have, in a number of prospective studies, been associated with cardiovascular morbidity and mortality in diabetes . Circulating levels of MBL are mainly determined genetically , and the MBL2 genotype with the highest level of MBL is associated with mortality in type 1 diabetes . Compared to MBL, the role of MASPs in diabetes remains less explored.…”

Section: Introductionmentioning

confidence: 99%

Plasma levels of MASP-1, MASP-3 and MAp44 in patients with type 2 diabetes: influence of glycaemic control, body composition and polymorphisms in the MASP1 gene

Krogh

Holt

Steffensen

et al. 2017

Clinical and Experimental Immunology

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Mounting evidence indicates that adverse activation of the complement system plays a role in the development of diabetic vascular complications. Plasma levels of the complement proteins mannan-binding lectin (MBL) and its associated serine proteases (MASP-1 and MASP-2) are elevated in diabetes. We hypothesized that single nucleotide polymorphisms (SNPs) in the MASP1 gene may contribute to altered plasma levels of the belonging gene products; MASP-1, MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44) in patients with type 2 diabetes. To investigate this, we compared plasma levels of MASP-1, MASP-3 and MAp44 in 100 patients with type 2 diabetes and 100 sex- and age-matched controls. Ten carefully selected SNPs were analysed using TaqMan genotyping assay. Additionally, we included a streptozotocin-induced diabetes mouse model to directly examine the effect of inducing diabetes on MASP-1 levels. MASP-1 levels were significantly higher among patients with type 2 diabetes compared with healthy controls (P = 0·017). Five SNPs (rs874603, rs72549254, rs3774275, rs67143992, rs850312) in the MASP1 gene were associated with plasma levels of MASP-1, MASP-3 and MAp44. In the diabetes mouse model, diabetic mice had significantly higher MASP-1 levels than control mice (P = 0·003). In conclusion, MASP-1 levels were higher among patients with type 2 diabetes and diabetic mice. The mechanism behind this increase remains elusive.

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“…Clinical observations through the last decade link the complement-activating carbohydrate-recognizing molecule mannan-binding lectin (MBL) to diabetic kidney disease [ 4 – 9 ]. In addition, we have recently described that the concentration-determining MBL genotype is tightly associated with mortality in type 1 diabetes patients [ 10 ]. Animal studies indicate a causal role of MBL in this association as MBL knockout mice are resistant to diabetic kidney changes [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Increased Autoreactivity of the Complement-Activating Molecule Mannan-Binding Lectin in a Type 1 Diabetes Model

Østergaard

Ruseva

Malik

et al. 2016

Journal of Diabetes Research

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Background. Diabetic kidney disease is the leading cause of end-stage renal failure despite intensive treatment of modifiable risk factors. Identification of new drug targets is therefore of paramount importance. The complement system is emerging as a potential new target. The lectin pathway of the complement system, initiated by the carbohydrate-recognition molecule mannan-binding lectin (MBL), is linked to poor kidney prognosis in diabetes. We hypothesized that MBL activates complement upon binding within the diabetic glomerulus. Methods. We investigated this by comparing complement deposition and activation in kidneys from streptozotocin-induced diabetic mice and healthy control mice. Results. After 20 weeks of diabetes, glomerular deposition of MBL was significantly increased. Diabetic animals had 2.0-fold higher (95% CI 1.6–2.5) immunofluorescence intensity from anti-MBL antibodies compared with controls (P < 0.001). Diabetes and control groups did not differ in glomerular immunofluorescence intensity obtained by antibodies against complement factors C4, C3, and C9. However, the circulating complement activation product C3a was increased in diabetes as compared to control mice (P = 0.04). Conclusion. 20 weeks of diabetes increased MBL autoreactivity in the kidney and circulating C3a concentration. Together with previous findings, these results indicate direct effects of MBL within the kidney in diabetes.

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Increased All-Cause Mortality in Patients With Type 1 Diabetes and High-Expression Mannan-Binding Lectin Genotypes: A 12-Year Follow-up Study

Cited by 27 publications

References 35 publications

Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin

Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin

Plasma levels of MASP-1, MASP-3 and MAp44 in patients with type 2 diabetes: influence of glycaemic control, body composition and polymorphisms in the MASP1 gene

Increased Autoreactivity of the Complement-Activating Molecule Mannan-Binding Lectin in a Type 1 Diabetes Model

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